Impaired T cell immunity and response to infection and immunization is a common feature in the elderly. We have previously shown that Asparagine (N) - linked protein glycosylation serves as a critical negative regulator of T cell immunity in both mice and humans. Virtually all cell surface and secreted proteins in animal cells are modified by the addition of complex carbohydrates in the ER/Golgi secretory pathway, providing molecular information not encoded in the genome. The branching and number of N-glycans per protein molecule cooperate to regulate binding to galectins, forming a molecular lattice that controls the distribution, clustering and endocytosis of surface glycoproteins in a predictable manner to affect cell growth and differentiation. Genetic and metabolic control of N-glyan branching negatively regulates T cell receptor clustering/signaling, enhances surface retention of the anti-inflammatory receptors Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) and Transforming Growth Factor - ? receptor (T?R) and inhibits pro-inflammatory TH1 and TH17 while promoting anti-inflammatory TH2 and induced T regulatory cell (iTreg) differentiation. Increasing N-glycan branching in T cells in vitro and in vivo by metabolically increasing substrate supply to Golgi enzymes via supplementation with the simple sugar N-acetylglucosamine (GlcNAc) suppresses T cell growth, enhances CTLA-4 and TGF-?RI/II surface expression, blocks TH1/TH17 differentiation and inhibits autoimmunity. Preliminary analysis suggests aging in humans and mice is associated with increases in serum GlcNAc levels and N-glycan branching in T cells, including na?ve, central and effector memory T cells. Indeed, hypo-proliferative in vitro responses in aged mouse and human T cells is rescued by down-regulating N-glycan branching using a small molecule Golgi inhibitor. We hypothesize that age-dependent increases in N-glycan branching significantly contributes to impaired T cell immunity and hypo-responsiveness to infection/immunization in the elderly. To confirm and expand on this hypothesis, the following aims are proposed. Aim 1 will confirm increased N-glycan branching in human T cell subsets of the elderly. Aim 2 will confirm that genetic and small molecule inhibition of N-glycan branching rejuvenates T cell responses in the elderly. Aim 3 examines the mechanism for age dependent increases in N-glycan branching, examining both genetic and metabolic regulation. Positive results will suggest down-regulation of N-glycan branching as a therapeutic strategy to rejuvenate T cell responses in the elderly.